CHOLERA, a VIRULENT, SOMETIMES lethal version of Montezuma’s Revenge, the diarrheal gut scourge bane of travelers, is commonly associated with pesky Vibrio bacteria; though similar symptoms are associated with the sometimes disease-causing and sometimes beneficial E. coli gut bacterium and many other intestinal tract microbes. Cholera is commonly controlled by an integrated management approach, often including proper sewage sanitation, water filtration, antibiotics, vaccines, rehydration therapy and the fortuitous presence of natural enemies known as phages.

Phages, short for bacteriophages, are ‘bacteria-eating’ viruses; the name phage is from the Greek word ‘phagein’, which means ‘to eat’. One might think of cholera as being like the black plague, a no longer relevant disease of the past. But a recent Google News search indicates lethal cholera outbreaks worldwide: From 54 dead in one month in Dar es Salaam, Tanzania, to Rwanda and Nigeria in Africa to Iraq in the Middle East and Haiti in the Americas; with worries about outbreaks in refugee camps worldwide where wars rage and after natural disasters such as earthquakes destroy sanitary infrastructure. In Iraq, “The epidemic is concentrated in the town of Abu Ghraib, situated about 25 kilometers (15 miles) west of the capital, Baghdad, where cholera has claimed at least 10 lives,” according to Iran’s Press TV. “Health Ministry spokesman Rifaq al-Araji has blamed the cholera epidemic in Iraq on low water levels in the Euphrates, noting that simmering temperatures during summer months may have activated the bacterium that causes the deadly disease…Cholera is an acute intestinal infection caused by ingestion of food or water contaminated with the bacterium Vibrio cholerae. It is a fast-developing infection that causes diarrhea, which can quickly lead to severe dehydration and death if treatment is not promptly provided.”

According to a “Major Article” in THE JOURNAL OF INFECTIOUS DISEASES: “Vibrio cholerae serogroup O1 and O139 organisms cause acute, watery diarrhea, with an estimated 100, 000–150, 000 deaths annually…Despite global efforts to improve drinking water quality and sanitation in developing countries, there has been little evidence of a decline in the global burden of cholera in recent years. Interest has therefore increased in the use of cholera vaccines as adjuncts to other preventive and therapeutic measures…Live oral cholera vaccines have the theoretical advantage of simulating infection by natural cholera. Experimental infection of North American volunteers has been shown to protect against cholera upon rechallenge…However, to date no live oral vaccine has conferred protection to cholera-endemic populations when tested in a randomized trial, suggesting that the predictions from studies of volunteers lacking preexisting immunity to cholera may not be readily generalizable to cholera-endemic populations.”

According to the United Nations News Centre: “A global stockpile of vaccines, funded by a number of international organizations and foundations, initially made 2 million doses of the vaccine available. In 2015, with additional funding from the GAVI Alliance, the number of doses available for use in both endemic hotspots and emergency situations is expected to rise to around 3 million. There are several examples in which the vaccine has stopped cholera outbreaks in their tracks, such as in South Sudan in 2014…But new outbreaks are ongoing in South Sudan and Tanzania” in 2015, indicating vaccines to produce natural immunity in conjunction with the best that can be done in the way of sanitation and clean water supplies is not enough. Using phages to produce natural biological control of the cholera bacterium, as part of a low-cost, integrated pest management approach, seems to have been totally and completely neglected, almost as if the successes of natural biocontrol of disease bacteria with phages from the years 1917 into the 1930s and continuing into the present in some parts of the world have been totally purged from the Western medical and public health history books. A costly neglect, in terms of human lives.

“Cholera generated as much horror and revulsion among Europeans as bubonic plague had before it, in part because of the blue-black shriveled appearance of its victims and in part because it could strike anyone without warning and kill in 4 to 6 hours,” according to an overview in Microbiological Reviews which implicated “sailors and colonists” in cholera’s global spread, not just poor sanitation (mixing sewage into drinking water supplies). “Although cholera is treatable with antibiotics and oral rehydration therapy (fluid and electrolyte replacement), it is nevertheless an extremely debilitating and sometimes fatal disease. The severe dehydration and cramps symptomatic of the disease are a consequence of the rapid, extreme loss of fluid and electrolytes during the course of the infection. The diarrhea is caused by the action of cholera toxin (CT), secreted by the bacterium Vibrio cholerae, although in some cases it may be caused by the related Escherichia coli heat-labile enterotoxin (LT).”

Historically, as mentioned in a previous blog post titled “Compost for Sustainable Soil Fertility & Disease Suppression,” Japanese cities adopted a more sustainable approach and thereby escaped the cholera epidemics afflicting London, Paris, India, the rest of Asia and the Americas: “Human waste, euphemistically called night soil, became a valuable soil fertility commodity in old Japan. Perhaps not quite worth its weight in gold, but a valuable commodity bought, sold, traded, and transported long distances from cities to farms. Rather than causing cholera and other diseases by entering the water supply as was common in European cities of the same era, sanitation and composting blessed Japan with multiple dividends…Farmers in old Japan spent their own money to build toilets and urinals along well-traveled roads for public use…” No doubt phages were also part of the integrated mix of methods providing natural biological control of cholera in old Japan, even if the invisibly small phages went unrecognized.

The 20th century use of phages for biological control of cholera and other disease bacteria was pioneered by the self-taught, French-Canadian microbiologist Felix d’Herelle, whose phage work was said by many to also be the foundation for modern molecular biology. An itinerant or journeyman scientist, who spent his life much like the modern-day post-doc, migrating from job to job around the world as he promoted phage therapy, d’Herelle was working with the Pasteur Institute in Paris while French and German troops were lining up against each other on the Western Front in World War I. In North Africa, as early as 1910, d’Herelle was pioneering the use of microbes to control biblical style locust plagues in North Africa, when he first noticed something killing the microbes used to kill the locusts; in other words, a complex ecosystem in which a higher level of natural enemies killed the lower-level natural enemies providing biological locust control.

During a World War I Paris dysentery outbreak, d’Herelle deduced that some patients were benefiting from phages invisibly providing biological control of the disease microbes. D’Herelle’s 1917 article on the subject for the French Academie des Sciences was titled “Sur un microbe invisible antagonistic des bacilles dysenterique” (“On an Invisible Microbe Antagonistic to Dysentery Bacteria”). “D’Herelle claimed that the antagonistic principle was filterable, living and organized, and hence a microbe,” wrote medical historian Ton Van Helvoort. D’Herelle “thought the living nature of the principle was proved by the possibility of transmitting it in a series of cultures of dysentery bacilli.”

Albert Einstein, who won a Nobel Prize for proving unseen forces and counter-intuitive phenomena based on mathematical constructs, agreed with d’Herelle. “The statistical explanation, which d’Herelle argued intuitively, is based on the properties of sampling that can be described by the mathematical expression known as the Poisson distribution,” wrote William Summers in his book, Felix d’Herelle and the Origins of Molecular Biology. “D’Herelle bolstered not only this argument but his own status with his well-known footnote giving Einstein’s opinion of this experiment: ‘In discussing this question with my colleague, Professor Einstein, he told me, as a physicist, he would consider this experiment as demonstrating the discontinuity of the bacteriophage. I was very glad to see how this deservedly-famous mathematician evaluated my experimental demonstration, for I do not believe that there are a great many biological experiments whose nature satisfies a physicist’…Since we have now presented the evidence proving the corpuscular nature of the bacteriophage we will no longer make use of such vague expressions as bacteriophage ‘liquid,’ ‘Fluid,’ or ‘filtrate,’ but will employ instead the more precise term’…The validity of the plaque counting assay and corpuscular nature of phage, however, would remain controversial and divide phage workers into two camps until the early 1940s.”

“The bacteriophage phenomenon was the observation that an abundant and therefore cloudy bacterial culture lysed within a short time to a clear solution under the influence of a filterable lytic ‘principle’,” wrote medical historian Ton van Helvoort. “The interpretation of this phenomenon gave rise to two main opposing positions, represented by Felix d’Herelle and Jules Bordet, who clashed heavily. In 1917, d’Herelle proposed the term “bacteriophage” for the lytic principle and was convinced it was to be characterized as a filterable virus which could lyse the bacterial culture. Therefore, this lysis was a virus disease of the bacteria which he named bacteriophagy. In the 1920s this interpretation was severely criticized by, among others, the bacteriologist and serologist Jules Bordet, who received the Nobel Prize for Medicine in 1919. Bordet’s view was that bacteriophagy was linked with the metabolism of the bacterium, while the involvement of a virus was rejected.” The dispute morphed into a personal vendetta against d’Herelle, whose strong personality was perhaps hated as much as his phage theories and his views on the dangers of vaccination that were considered heretical by the era’s Nobel Prize-winning immunologists.

According to medical historian Dottore Emiliano Fruciano: “In presenting his concepts to the scientific and world community, d’Herelle connected his phage interventions to a theoretical system that clashed with those held by institutional medical science. d’Herelle thought that the reason for natural recovery was not the humoral and cellular mechanisms activated by the immune system, but rather the presence of a virulent phage for the pathogenic bacterium in the host. His observations led him to believe that phage was a common guest of every organism from man to silkworm…d’Herelle concluded that phage was the exogenous agent of natural recovery, leading to ‘spontaneous recovery’…

“Recovery was a case of the prevalence of phage over the bacterium, and death was a case of the prevalence of bacterium over phage,” wrote Fruciano. “Furthermore, d’Herelle hypothesized that phage was able to spread among ill people, mainly via stool; thus, a lack of hygiene, while contributing to infection, would also lead to recovery; phage would have been the reason for the end of epidemics. This characteristic made phage, the recovery agent, transmissible between individuals, just like the agent of disease…

“In support of his theory of natural recovery, d’Herelle cited exemplary phenomena, including recovery following exposure to cholera. In cholera, patients generally convalesced after two or three days (sometimes within 12 hours) of initial symptoms; even ‘artificial’ recoveries through phage therapy often occurred after 24 hours. However, according to d’Herelle, observations from many animal diseases had demonstrated that it took many more days for immunity to become effective in the fight against infection. To explain natural recovery through the mechanisms of immunity was not possible because of the timing.

“Moreover, in diseases such as typhus and plague, which are characterized by strong immunity, relapses were possible during convalescence. This would mean that the patient, although convalescing, was still not immune. In these kinds of pathologies, typically typhus and plague, immunity usually lasts forever, yet immunity only comes into play 20 days following convalescence. According to d’Herelle, ‘Immunity, far from being the cause of recovery, is a consequence of recovery’. Further confirmation of d’Herelle’s theory was given by the statistics of the three hospitals in Calcutta, India. Paradoxically, the lowest rate of mortality for cholera (27%) was recorded at the hospital for poor people, the Campbell Hospital, while the highest rate of mortality (86%) was recorded at a hospital for rich people, the European Hospital – a hospital recognized in 1926 for its wealthy patients and hygienic conditions. There were fewer deaths at the hospital where care and hygiene were poor, that is, where the possibility for the development and dissemination of virulent phage or the recovery agent were best.”

The cholera and phage biocontrol case in general became intolerably heretical to many in the scientific medical establishment, what with d’Herelle’s warnings against the dangers of conventional vaccinations and the radical challenge to conventional consensus medical theories supported by immunologists who had won Nobel Prizes in medicine, said Fruciano: “According to d’Herelle, immunity and recovery were two different processes; only after the bacteriolytic action of phage could immunity be developed. Furthermore, there were two kinds of immunity: heterologous immunity, linked to the presence of phage activity against the pathogen, and homologous immunity, linked to immune system activity.

“…man contracts cholera because his immune system is not able to neutralize the bacterium. In d’Herelle’s opinion, in the case of patients with cholera, recovery occurs because of the presence of a virulent phage for Vibrio cholerae as a result of heterologous immunity, not because of natural or homologous immunity. d’Herelle found that the administration of phage resulted not only in a quick recovery, but also lasting immunity. He also asserted that a suspension of phage had strong immunizing power (here in the traditional sense) because the bacterial substances dissolved by phage action induced immune system reactions… d’Herelle’s findings were contrary to the conclusions of Metchnikoff, Bordet and Ehrlich, the founders of immunology…phage therapy efficacy would have required a revision of the current explanation of natural recovery…In other words, the proof of efficacy of phage therapy was equivalent to the proof of the truthfulness of d’Herelle’s heretical theories. Thus, to verify the efficacy of phage therapy and prevention measures, the principles of modern medicine were at stake; this was a paradigm shift for the scientific community.”

Of course, in the early years of the 20th century, prior to the invention of the electron microscope to provide visual evidence, the immunologists could plausibly argue against the existence of phages (despite Einstein’s endorsement); and in the absence of modern genomics, indeed before DNA and RNA were implicated in heredity, matching the right mixture of phages with a particular disease bacterium was perhaps more art than science, an art in continuous successful practice in just a few places such as the ex-Soviet Republics of Georgia and Russia, and Poland. Also, early 20th century medical experiments are not considered rigorous by current standards. All of which makes the several hundred successful phage experiments and interventions against cholera, plague, typhus and other diseases subject to blanket dismissal; and, hence, the absence of natural biological control from Western medical practices, medical schools, and institutional research agendas.

“The following details some of the most sensational results in phage prophylaxis that would seem to contradict the eventual dismissal of d’Herelle’s works,” stated Fruciano. “In 1927, an epidemic of Asiatic cholera was halted at its start in several villages with 2000 to 3000 Punjabi inhabitants via two methods of phage prophylaxis delivery: the first was the addition of potent, individually dosed phage preparations, and the second was the administration of phage prophylaxis to local water supplies. In both scenarios, the epidemic was terminated within 48 hours; in the past, the same result was achieved through traditional interventions within a 26-day time period.

“…at the St Mary Hospital in London, England, where penicillin was first discovered, Himmelweit developed a cross-therapy involving a combination of phage and penicillin to reduce the possibility of penicillin-resistant bacteria. This solution was very promising…Above all, the conjoined administration of phage and penicillin gave positive outcomes in clinical trials. It is likely that this experimental solution worked well because, as it is known today, the mechanisms by which phage and penicillin kill bacteria are different. Unfortunately, this alternative use of phage, in combination with penicillin, has been abandoned. Why has this possibility been forgotten despite the fact that antibiotic-resistant bacteria appeared as soon as penicillin was introduced into medical practice?

“…Summers, a historian of medicine who delved deeply into d’Herelle’s scientific works, speaks of the “Soviet Taint” as a plausible reason for the lack of interest in phage as an antimicrobial agent. Following World War II, phage therapy research continued only in eastern European countries, and “d’Herelle’s Cure” became “Stalin’s Cure”. According to Summers, phage therapy and prophylactic measures became ideological symbols of divisions and disagreements between western and eastern countries, partially explaining the lack of interest in phage as an antibacterial agent in Western medical science.”